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Krifka Publikation Glanzlicht 09 This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Biomaterials 32 (2011) 1787e1795 Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials Activation of stress-regulated transcription factors by triethylene glycol dimethacrylate monomer Stephanie Krifka a, Christine Petzel a, Carola Bolay a, Karl-Anton Hiller a, Gianrico Spagnuolo b, Gottfried Schmalz a, Helmut Schweikl a,* a Department of Operative Dentistry and Periodontology, University of Regensburg, D-93042 Regensburg, Germany b Department of Oral and Maxillofacial Sciences, University of Naples “Federico II”, Italy article info abstract Article history: Triethylene glycol dimethacrylate (TEGDMA) is a resin monomer available for short exposure scenarios of Received 22 October 2010 oral tissues due to incomplete polymerization processes of dental composite materials. The generation of Accepted 14 November 2010 reactive oxygen species (ROS) in the presence of resin monomers is discussed as a common mechanism Available online 10 December 2010 underlying cellular reactions as diverse as disturbed responses of the innate immune system, inhibition of dentin mineralization processes, genotoxicity and a delayed cell cycle. Yet, the signaling pathway Keywords: through a network of proteins that finally initiates the execution of monomer-induced specific cell Resin monomer responses is unknown so far. The aim of the present study was to extend the knowledge of molecular TEGDMA Stress response mechanisms of monomer-induced cell death as a basis for reasonable therapy strategies. Thus, the Transcription factor monomer-induced expression and phosphorylation of stress-related transcription factors was analyzed in various cell lines. The time-related induction of apoptosis was investigated as well. The expression of p53 increased in HeLa cell cultures treated with camptothecin (positive control) for 24h, and the formation of p53Ser15 and p53Ser46 was detected in cell nuclei by Western blotting. TEGDMA (3 mM) appeared to stimulate p53 expression only slightly, but increased p21 expression was found in cell nuclei and cytoplasm. Both camptothecin and TEGDMA increased p53 expression to some extent in the nuclear fraction in human transformed pulp-derived cells (tHPC), and similar effects were detected in RAW264.7 macrophages. No clear induction of c-Jun and phospho-c-Jun by TEGDMA was detected in HeLa cell nuclei, and the expression of ATF-2 and phospho-ATF-2 was inhibited in the presence of the monomer. ATF-3 expression was found only in the nuclear fraction of camptothecin-treated HeLa cultures. TEGDMA seemed to inhibit the formation of phospho-c-Jun and phospho-ATF-2 in tHPC, and the monomer acted negatively on the expression of c-Jun, ATF-2 and ATF-3 in RAW264.7 macrophages. These changes in the expression and activation of stress-related transcription factors were time-related to the induction of apoptosis by TEGDMA in all cell lines. The present study provides experimental evidence that TEGDMA interferes with the regulation of cellular pathways through transcription factors activated as a conse- quence of DNA damage like p53 or initiated downstream of MAPK (mitogen-activated protein kinases) like c-Jun, ATF-2 and ATF-3. The direct causal correlation between DNA damage, activation or inhibition of MAPKs and transcription factors, and apoptosis is under current investigation. However, the induction of apoptosis in different cell lines in the presence of monomers like TEGDMA may be subject to a higher level of complexity than currently suggested by simple linear models. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction composite materials are not chemically inert in the human oral cavity. Residual unreacted monomers are available for short expo- Tissues of the oral cavity are impacted by a variety of biological sure scenarios due to incomplete polymerization processes of the stressors including compounds released from dental restorative organic matrix of dental composites. Triethylene glycol dimetha- biomaterials. Numerous investigations have shown that dental crylate (TEGDMA) was found to be a major comonomer eluted even from polymerized resin composites in an aqueous environment [1]. In addition, polymerized composites are also susceptible to * Corresponding author. Fax: þ49 941 944 6025. biodegradation through hydrolytic enzymes in saliva, making the E-mail address: [email protected] (H. Schweikl). 0142-9612/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2010.11.031 Author's personal copy 1788 S. Krifka et al. / Biomaterials 32 (2011) 1787e1795 polymeric network most likely a source of continuous release of Besides the suggested role of MAPKs in the regulation of cell compounds to which cells and tissues are then exposed for a long death and survival, the function of the tumor suppressor p53 as period of time [2]. a key regulator of apoptosis is firmly established [18]. P53 is acti- Among others, the resin monomers TEGDMA and HEMA caused vated through the ATM signaling pathway when DNA damage specific stress responses in a wide variety of eukaryotic cells in vitro occurs and, in addition to many other functions, acting as a tran- [3]. These substances induced cell death via apoptosis in various cell scription factor controls cell cycle progression and apoptosis-related types including pulp and gingiva cells and it appears as if cell death gene expression or interacts with proteins after posttranslational was mediated, at least in part, by the generation of reactive oxygen modifications including phosphorylation at Ser15 and Ser46 resi- species (ROS) disturbing the redox balance [4,5]. Furthermore, dues. Among the p53 target genes, p21Cip1 expression is activated, genotoxic and mutagenic effects caused by TEGDMA are probably to which in turn acts as an inhibitor of cell proliferation or apoptosis some extent a consequence of ROS-induced DNA damage. A signif- depending on its cellular localization [19]. icant increase in the levels of 8-oxoguanine as a marker for oxidative Although not experimentally proven so far, it has been proposed DNA damage was found in cell cultures after long exposure to that an increase in ROS caused by resin monomers is the main origin TEGDMA [6]. As a result of DNA damage, mammalian cells activate of the upstream activation of MAPK [17]. In contrast, the related functional cell cycle checkpoints through the coordinated activities downstream activation of MAPK-related gene expression of specific of regulatory proteins. A corresponding monomer-induced delay of transcription factors that finally initiate the execution of monomer- the cell cycle was, however, overridden in the presence of the induced apoptosis is unknown to date. The activation of cascades of antioxidant N-acetylcysteine (NAC) [7,8]. Furthermore, low phosphorylation, in many cases increases expression of immediate TEGDMA concentrations and chemically related substances like early genes as an early stress response. These immediate early genes PMMA (poly-methyl methacrylate) even inhibited specific odonto- code for transcription factors, which then regulate downstream blast functions including alkaline phosphatase activity, the matrix genes of the cell survival network [20]. Therefore, it was the aim of mineralizing capability, calcium deposition, and gene expression, the present study to broaden our understanding of the molecular such as dentin sialoprotein [9,10]. Oxidative stress is most likely the mechanisms of dental resin monomer-induced cell death. To this cause of disturbed mineralization because NAC dramatically end, we analyzed the monomer-induced expression and phos- reduced cytotoxicity of bone substitutes to maintain osteoblastic phorylation of transcription factors that were associated with the viability and function, implying enhanced bone regeneration induction of apoptosis. around NAC-treated inorganic biomaterials [11]. The monomer First, we hypothesized that the induction of apoptosis may TEGDMA also influenced specific cell responses of the innate depend on a differential activation of various transcription factors immune system. The monomer instantaneously downregulated the which are targets of the MAPK signaling pathway. For instance, the LPS-induced cytokine production in macrophages and inhibited the activity of the transcription factor AP-1 is rapidly elevated due to expression of surface antigens like CD14 and others surface markers the induction of fos and jun gene transcription by many stimuli essential for the controlled interaction of immune cells [12]. including genotoxic agents [21,22]. In addition to the activation at These findings clearly indicate that the adverse effects of resin the transcriptional level, the activity of c-Jun is greatly enhanced in monomers involve
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